The long-term goal of the proposal is to define the cellular processes that regulate proliferation, differentiation, and gene expression in the intestine. The fundamental premise is that cyclin-dependent kinase inhibitors are activated when intestinal stem cells become activated crypt cells. One such cyclin-dependent kinase inhibitor is p27 which may act independently from G1 cyclins and cdks. In addition, multiple redundant genes control proliferation and differentiation, apart from p27. Therefore, the proposed studies will focus upon inhibiting p27 to assess effects upon differentiation; to elucidate the role of Jab 1 in the regulation of p27 expression; to correlate differentiation-inducing properties of p27 with a subdomain of the protein; to identify p27 interacting proteins and to determine their expression in vitro and in vivo; and to continue identification of novel genes that regulate intestinal differentiation.